No intervention is currently available to prevent the consequences of organ damage associated with cardiopulmonary arrest. While the protective effects of preconditioning (PC) during regional ischemic injury to several organs have been well-documented, it remains unknown whether this phenomenon can be utilized to improve the outcome following cardiac arrest. The overall objective of this proposal is to evaluate the efficacy of physiologic and pharmacologic late PC-mimetic interventions in preventing cardiac and neuronal injury during cardiopulmonary arrest. Our fundamental hypothesis is that the heart and brain can be preconditioned to tolerate the ischemic injury during cardiac arrest by using clinically-feasible PC-mimetic interventions that can be given prophylactically to patients at risk for cardiopulmonary arrest. Specifically, we will test the hypothesis that exposure to exercise, adenosine A1 receptor agonists, opioid ?1 receptor agonists, and NO donors induces delayed antistunning and antiapoptotic effects that result in improved outcome following cardiopulmonary arrest, and that these salubrious effects are mediated by a coordinated upregulation of iNOS, COX-2, and HO-1. This study will utilize a broad multidisciplinary approach that will involve integrative physiology, protein chemistry, molecular biology, and gene targeting. All studies will be carried out in a well-characterized mouse model of cardiac arrest using genetically-engineered animals, which will provide conclusive information. In Aim 1, the efficacy of exercise, CCPA, TAN-67, and DETA/NO in conferring protection during cardiac arrest will be carefully characterized and the mechanism of the antiapoptotic effects will be elucidated. Aim 2 will investigate the role of iNOS in organ protection during cardiopulmonary arrest. Both iNOS-/- and iNOS transgenic mice will be used to determine whether iNOS is necessary and sufficient to confer protection. In Aim 3, the beneficial role of COX-2 will be conclusively established by genetic ablation and pharmacologic inhibition. Aim 4 will elucidate the role of HO-1 as a co-mediator of protection using HO-1-/- mice and HO-1 transgenic mice. Aim 5 will determine the utility of adenovirus-mediated gene transfer of iNOS, COX-2, and HO-1 in recapitulating the beneficial effects. This proposal will yield new and important information regarding the role of clinically-relevant agents in inducing protection against a devastating and common health problem. This information may eventually lead to the development of novel therapeutic strategies to save human lives. PUBLIC HEALTH RELEVANCE Approximately 500,000 Americans are affected by cardiopulmonary arrest every year. Despite decades of research, the survival and prognosis after cardiac arrest remain dismal. Although the phenomenon of preconditioning (PC) has been shown to protect various organs during ischemic injury, its role in cardiac arrest remains unclear. The primary goal of this proposal is to examine whether PC-mimetic physiologic and pharmacologic interventions can protect against cardiac and neurologic injury sustained during cardiac arrest. These results would have enormous therapeutic implications for patients with cardiac arrest. The results of the proposed studies will therefore be highly relevant for improving public health, and improving the length and quality of life of thousands of patients with cardiac arrest.